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Toll-like receptors (TLRs) sense pathogen-associated molecular patterns to activate the production of inflammatory mediators. TLR4 recognizes lipopolysaccharide (LPS) and drives the secretion of inflammatory cytokines, often contributing to sepsis. We report that transient receptor potential melastatin-like 7 (TRPM7), a non-selective but Ca2+-conducting ion channel, mediates the cytosolic Ca2+ elevations essential for LPS-induced macrophage activation. LPS triggered TRPM7-dependent Ca2+ elevations essential for TLR4 endocytosis and the subsequent activation of the transcription factor IRF3. In a parallel pathway, the Ca2+ signaling initiated by TRPM7 was also essential for the nuclear translocation of NFκB. Consequently, TRPM7-deficient macrophages exhibited major deficits in the LPS-induced transcriptional programs in that they failed to produce IL-1β and other key pro-inflammatory cytokines. In accord with these defects, mice with myeloid-specific deletion of Trpm7 are protected from LPS-induced peritonitis. Our study highlights the importance of Ca2+ signaling in macrophage activation and identifies the ion channel TRPM7 as a central component of TLR4 signaling.TRPM7 is essential for LPS-induced macrophage activationTRPM7 mediates the Ca2+ influx necessary for TLR4 endocytosisLPS-induced phosphorylation and translocation of NFκB p65 and IRF3 depend on TRPM7Mice with a myeloid-specific Trpm7 deletion are resistant to LPS-induced peritonitisSchappe et al. show that genetic deletion of Trpm7 in macrophages or pharmacological inhibition of TRPM7 channel prevents macrophage activation due to the loss of TRPM7-mediated Ca2+ influx in response to LPS. The study identifies TRPM7 as a Ca2+-entry pathway required for macrophage activation.